Dynamic balance of pro‐ and anti‐inflammatory signals controls disease and limits pathology

Abstract

Immune responses to pathogens are complex and not well understood in many diseases, and this is especially true for infections by persistent pathogens. One mechanism that allows for long-term control of infection while also preventing an over-zealous inflammatory response from causing extensive tissue damage is for the immune system to balance pro- and anti-inflammatory cells and signals. This balance is dynamic and the immune system responds to cues from both host and pathogen, maintaining a steady state across multiple scales through continuous feedback. Identifying the signals, cells, cytokines, and other immune response factors that mediate this balance over time has been difficult using traditional research strategies. Computational modeling studies based on data from traditional systems can identify how this balance contributes to immunity. Here we provide evidence from both experimental and mathematical/computational studies to support the concept of a dynamic balance operating during persistent and other infection scenarios. We focus mainly on tuberculosis, currently the leading cause of death due to infectious disease in the world, and also provide evidence for other infections. A better understanding of the dynamically balanced immune response can help shape treatment strategies that utilize both drugs and host-directed therapies.

Molecular Mechanisms Controlling Foxp3 Expression in Health and Autoimmunity: From Epigenetic to Post-translational Regulation

“…A fine regulation of the intensity and duration of the immune response during inflammation is necessary to avoid tissue damage (200). Treg cells are crucial for maintaining immune homeostasis and prevent autoimmune diseases; on the other hand, their activity during an acute infection must be temporarily downregulated to allow adequate immune response against foreign pathogens.…”

TLR4 signaling and macrophage inflammatory responses are dampened by GIV/Girdin

“…The major discovery we report here is how macrophages confine TLR4 signaling and prevent an overzealous inflammatory response using a multi-modular scaffold, GIV. Prior work has eluded that balanced immune responses are brought about when the immune system dynamically responds to cues from both host and pathogen across multiple scales (47) By elucidating the role of GIV, a non-canonical GEF for Gαi proteins, our findings also provide insights into a hitherto unknown mechanism of signal integration and convergence between TLRs and heterotrimeric G proteins. The role of the G-protein coupled receptor (GPCR)→G protein→cAMP signaling cascade in macrophage differentiation and in shaping macrophage responses to pathogens and injury-related danger molecules is well recognized (48).…”

The Antitumor Efficacy of β-Elemene by Changing Tumor Inflammatory Environment and Tumor Microenvironment

“…When a pathogen enters the host, it causes damage to the organism and activates the immune system [32,33]. Moreover, a large number of inflammatory cells, such as tumor-related macrophages and dendritic cells, infiltrate and activate [34]. These cells also promote each other with tumor-related inflammatory cells, which results in a variety of tumorigenic factors in the tumor microenvironment [35].…”